IMPORTANCE: It remains uncertain whether vitamin C routinely used with oral iron supplements is essential for patients with iron deficiency anemia (IDA). OBJECTIVE: To compare the equivalence and assess the safety of oral iron supplements plus vitamin C or oral iron supplements alone in patients with IDA. DESIGN, SETTING, AND PARTICIPANTS: This single-center, open-label, equivalence randomized clinical trial was conducted from January 1, 2016, to December 30, 2017, in Huashan Hospital, Fudan University. Adult patients with newly diagnosed IDA were enrolled. Participants were randomly assigned (1:1) to the oral iron supplements plus vitamin C group or the oral iron supplements-only group. Data analysis was performed from March to December 2018. INTERVENTIONS: Patients were randomized to receive a 100-mg oral iron tablet plus 200 mg of vitamin C or a 100-mg iron tablet alone every 8 hours daily for 3 months. MAIN OUTCOMES AND MEASURES: The primary outcome was the change in hemoglobin level from baseline to 2 weeks of treatment, and an equivalence margin of 1 g/dL in hemoglobin was chosen for the demonstration of comparable efficacy. Secondary outcomes included the change in the reticulocyte percentage after 2 weeks of treatment, the increase in hemoglobin level after 4 weeks of treatment, the increase in serum ferritin level after 8 weeks of treatment, and adverse events. RESULTS: Among the 440 randomized patients (220 each in the oral iron supplements plus vitamin C group and iron-only group; 426 women [96.8%]; mean [SD] age, 38.3 [11.7] years), all were assessed for the primary outcome, and 432 (98.2%) completed the trial. From baseline to the 2-week follow-up, the mean (SD) change in hemoglobin level was 2.00 (1.08) g/dL in the oral iron supplements plus vitamin C group and 1.84 (0.97) g/dL in the oral iron supplements-only group (between-group difference, 0.16 g/dL; 95% CI, -0.03 to 0.35 g/dL), thus meeting the criteria for equivalence. The mean (SD) change in serum ferritin level from baseline to 8-week follow-up was 35.75 (11.52) ng/mL in the vitamin C plus iron group and 34.48 (9.50) ng/mL in the iron-only group (between-group difference, 1.27 ng/mL; 95% CI, -0.70 to 3.24 ng/mL; P = .21). There were no significant differences between the 2 groups regarding the rates of adverse events (46 [20.9%] vs 45 [20.5%]; difference, 0.4%; 95% CI, -6.7% to 8.5%; P = .82). No patient withdrew because of adverse events. CONCLUSIONS AND RELEVANCE: Among patients with IDA, oral iron supplements alone were equivalent to oral iron supplements plus vitamin C in improving hemoglobin recovery and iron absorption. These findings suggest that on-demand vitamin C supplements are not essential to take along with oral iron supplements for patients with IDA. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02631668.